tbuckley/cabot-search huggingface dataset:
ZipperCells Exhibit Enhanced Accumulation and Retention at the Site of Myocardial Infarction
Authors: Natalie E. Jasiewicz, Kuo‐Ching Mei, Hannah M. Oh, Parth Chansoria, Dylan A. Hendy, Emily E. Bonacquisti, Eric M. Bachelder, Kristy M. Ainslie, Haifeng Yin, Li Qian, Brian C. Jensen, Juliane Nguyen
Journal: Advanced Healthcare Materials (2022)

Abstract There has been extensive interest in cellular therapies for the treatment of myocardial infarction, but bottlenecks concerning cellular accumulation and retention remain. Here, a novel system of in situ crosslinking mesenchymal stem cells (MSCs) for the formation of a living depot at the infarct site is reported. Bone marrow‐derived mesenchymal stem cells that are surface decorated with heterodimerizing leucine zippers, termed ZipperCells, are engineered. When delivered intravenously in sequential doses, it is demonstrated that ZipperCells can migrate to the infarct site, crosslink, and show ≈500% enhanced accumulation and ≈600% improvement in prolonged retention at 10 days after injection compared to unmodified MSCs. This study introduces an advanced approach to creating noninvasive therapeutics depots using cellular crosslinking and provides the framework for future scaffold‐free delivery methods for cardiac repair.
The Effect of a Neuronal Nitric Oxide Synthase Inhibitor on Neurovascular Regulation in Humans
Authors: Kevin O’Gallagher, Ryan E. Rosentreter, Jan Elaine Soriano, Ali Roomi, Saqib Saleem, Tyler Lam, Roman Roy, Grant R. Gordon, Satish R. Raj, Philip J. Chowienczyk, Ajay M. Shah, Aaron A. Phillips
Journal: Circulation Research (2022)

Neurovascular coupling (NVC) is a key process in cerebral blood flow regulation. NVC ensures adequate brain perfusion to changes in local metabolic demands. Neuronal nitric oxide synthase (nNOS) is suspected to be involved in NVC; however, this has not been tested in humans. Our objective was to investigate the effects of nNOS inhibition on NVC in humans.We performed a 3-visit partially randomized, double-blinded, placebo-controlled, crossover study in 12 healthy subjects. On each visit, subjects received an intravenous infusion of either S-methyl-L-thiocitrulline (a selective nNOS-inhibitor), 0.9% saline (placebo control), or phenylephrine (pressor control). The NVC assessment involved eliciting posterior circulation hyperemia through visual stimulation while measuring posterior and middle cerebral arteries blood velocity.nNOS inhibition blunted the rapidity of the NVC response versus pressor control, evidenced by a reduced initial rise in mean posterior cerebral artery velocity (-3.3% [-6.5, -0.01], P=0.049), and a reduced rate of increase (ie, acceleration) in posterior cerebral artery velocity (slope reduced -4.3% [-8.5, -0.1], P=0.045). The overall magnitude of posterior cerebral artery response relative to placebo control or pressor control was not affected. Changes in BP parameters were well-matched between the S-methyl-L-thiocitrulline and pressor control arms.Neuronal NOS plays a role in dynamic cerebral blood flow control in healthy adults, particularly the rapidity of the NVC response to visual stimulation. This work opens the way to further investigation of the role of nNOS in conditions of impaired NVC, potentially revealing a therapeutic target.
One‐Pot Facile Encapsulation of Dimethyloxallyl Glycine by Nanoscale Zeolitic Imidazolate Frameworks‐8 for Enhancing Vascularized Bone Regeneration
Authors: Xin Zhang, Jun‐Yu Chen, Xiang Pei, Ya‐Hong Li, Hao Feng, Zi‐Han He, Wen‐Jia Xie, Xi‐Bo Pei, Zhou Zhu, Qian‐Bing Wan, Jian Wang
Journal: Advanced Healthcare Materials (2022)

In the process of bone tissue regeneration, regulation of osteogenesis-angiogenesis coupling is of great importance. Therefore, dimethyloxallyl glycine (DMOG) is loaded by nanoscale zeolitic imidazolate frameworks-8 (ZIF-8) to obtain a drug-loading system that can promote osteogenesis-angiogenesis coupling. Characterization of the drug-loading nanoparticles (DMOG@ZIF-8) reveals that DMOG is successfully loaded into ZIF-8 by two different methods, and the DMOG@ZIF-8 is prepared using the one-pot method (OD@ZIF-8) achieves higher loading efficiency and longer release time than those prepared using the post-loading method (PD@ZIF-8). In vitro studies found that DMOG@ZIF-8 significantly enhances the migration, tube formation, and angiogenesis-related protein secretion of human umbilical vein endothelial cells as well as the extracellular matrix mineralization, alkaline phosphatase activity, and osteogenesis-related protein secretion of bone marrow mesenchymal stem cells. Moreover, OD@ZIF-8 nanoparticles are more efficient than PD@ZIF-8 nanoparticles in induction of osteogenesis-angiogenesis coupling. Then, in vivo cranial critical defect model shows that the addition of OD@ZIF-8 significantly promotes vascularized bone formation as indicated by the results including microcomputed tomographic, histological and immunofluorescence staining, and so on. Taken together, loading ZIF-8 with DMOG may be a promising solution for critical-sized bone defect reconstruction and the one-pot method is preferred in the preparation of such drug-loading system.
Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma
Authors: Xi-Ya Li, Ji-Chuan Wu, Ping Liu, Zi-Juan Li, Yong Wang, Bing-Yi Chen, Cheng-Long Hu, Ming-Yue Fei, Peng-Cheng Yu, Yi-Lun Jiang, Chun-Hui Xu, Bin-He Chang, Xin-Chi Chen, Li-Juan Zong, Jia-Ying Zhang, Ying Fang, Xiao-Jian Sun, Kai Xue, Li Wang, Shu-Bei Chen, Shi-Yu Jiang, Ai-ling Gui, Ling Yang, Juan J. Gu, Bao-Hua Yu, Qun-ling Zhang, Lan Wang
Journal: Leukemia (2022)

The patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL) have poor prognosis, and a novel and effective therapeutic strategy for these patients is urgently needed. Although ubiquitin-specific protease 1 (USP1) plays a key role in cancer, the carcinogenic effect of USP1 in B-cell lymphoma remains elusive. Here we found that USP1 is highly expressed in DLBCL patients, and high expression of USP1 predicts poor prognosis. Knocking down USP1 or a specific inhibitor of USP1, pimozide, induced cell growth inhibition, cell cycle arrest and autophagy in DLBCL cells. Targeting USP1 by shRNA or pimozide significantly reduced tumor burden of a mouse model established with engraftment of rituximab/chemotherapy resistant DLBCL cells. Pimozide significantly retarded the growth of lymphoma in a DLBCL patient-derived xenograft (PDX) model. USP1 directly interacted with MAX, a MYC binding protein, and maintained the stability of MAX through deubiquitination, which promoted the transcription of MYC target genes. Moreover, pimozide showed a synergetic effect with etoposide, a chemotherapy drug, in cell and mouse models of rituximab/chemotherapy resistant DLBCL. Our study highlights the critical role of USP1 in the rituximab/chemotherapy resistance of DLBCL through deubiquitylating MAX, and provides a novel therapeutic strategy for rituximab/chemotherapy resistant DLBCL.
Macrophage membrane-coated nanovesicles for dual-targeted drug delivery to inhibit tumor and induce macrophage polarization
Authors: Xin Huang, Lutong Wang, Haoyu Guo, Weiyue Zhang
Journal: Bioactive Materials (2022)

Immunosuppressive M2 macrophages in the tumor microenvironment (TME) can mediate the therapeutic resistance of tumors, and seriously affect the clinical efficacy and prognosis of tumor patients. This study aims to develop a novel drug delivery system for dual-targeting tumor and macrophages to inhibit tumor and induce macrophage polarization.The anti-tumor effects of methyltransferase like 14 (METTL14) were investigated both in vitro and in vivo. The underlying mechanisms of METTL14 regulating macrophages were also explored in this study. We further constructed the cyclic (Arg-Gly-Asp) (cRGD) peptide modified macrophage membrane-coated nanovesicles to co-deliver METTL14 and the TLR4 agonist.We found that METTL14 significantly inhibits the growth of tumor in vitro. METTL14 might downregulate TICAM2 and inhibit the Toll-like receptor 4 (TLR4) pathway of macrophages, meanwhile, the combination of METTL14 and the TLR4 agonist could induce M1 polarization of macrophages. Macrophage membrane-coated nanovesicles are characterized by easy modification, drug loading, and dual-targeting tumor and macrophages, and cRGD modification can further enhance its targeting ability. It showed that the nanovesicles could improve the in vivo stability of METTL14, and dual-target tumor and macrophages to inhibit tumor and induce M1 polarization of macrophages.This study anticipates achieving the dual purposes of tumor inhibition and macrophage polarization, and providing a new therapeutic strategy for tumors.
A Phase I/II Open-Label Study of Molibresib for the Treatment of Relapsed/Refractory Hematologic Malignancies
Authors: Mark A. Dawson, Gautam Borthakur, Brian J.P. Huntly, Anastasios Karadimitris, Adrian Alegre, Aristeidis Chaidos, Dan T. Vogl, Daniel A. Pollyea, Faith E. Davies, Gareth J. Morgan, Jacob L. Glass, Manali Kamdar, Maria-Victoria Mateos, Natalia Tovar, Paul Yeh, Regina García Delgado, Faisal Basheer, Ludovica Marando, Paolo Gallipoli, Anastasia Wyce, Anu Shilpa Krishnatry, Olena Barbash, Evi Bakirtzi, Geraldine Ferron-Brady, Natalie O. Karpinich, Michael T. McCabe, Shawn W. Foley, Thierry Horner, Arindam Dhar, Brandon E. Kremer, Michael Dickinson
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Molibresib is a selective, small molecule inhibitor of the bromodomain and extra-terminal (BET) protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851). Patients and Methods: Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), Non–Hodgkin lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T-cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR). Results: There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg daily (for MDS) and 60 mg daily (for CTCL) were selected. Most common Grade 3+ adverse events included thrombocytopenia (37%), anemia (15%), and febrile neutropenia (15%). Six patients achieved complete responses [3 in Part 1 (2 AML, 1 NHL), 3 in Part 2 (MDS)], and 7 patients achieved partial responses [6 in Part 1 (4 AML, 2 NHL), 1 in Part 2 (MDS)]. The ORRs for Part 1, Part 2, and the total study population were 10% [95% confidence interval (CI), 4.8–18.7], 25% (95% CI, 7.3–52.4), and 13% (95% CI, 6.9–20.6), respectively. Conclusions: While antitumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.
Covid-19 vaccination in the UK: the Joint Committee on Vaccination and Immunisation’s infrastructure
Authors: Mark N Upton
Journal: BMJ (2022)

Upton MN.Where is the evidence that extending the dosing interval for the Pfizer mRNA vaccine from 3 weeks to 12 weeks is effective and safe?[response to Mahase E. Covid-19: Order to reschedule and delay second vaccine dose is "totally unfair," says BMA].
Co-immunization with hemagglutinin stem immunogens elicits cross-group neutralizing antibodies and broad protection against influenza A viruses
Authors: Syed M. Moin, Jeffrey C. Boyington, Seyhan Boyoglu-Barnum, Rebecca A. Gillespie, Gabriele Cerutti, Crystal Sao-Fong Cheung, Alberto Cagigi, John R. Gallagher, Joshua Brand, Madhu Prabhakaran, Yaroslav Tsybovsky, Tyler Stephens, Brian E. Fisher, Adrian Creanga, Sila Ataca, Reda Rawi, Kizzmekia S. Corbett, Michelle C. Crank, Gunilla B. Karlsson Hedestam, Jason Gorman, Adrian B. McDermott, Audray K. Harris, Tongqing Zhou, Peter D. Kwong, Lawrence Shapiro, John R. Mascola, Barney S. Graham, Masaru Kanekiyo
Journal: Immunity (2022)
Assessing How Social Exposures Are Integrated in Exposome Research: A Scoping Review
Authors: Lola Neufcourt, Raphaële Castagné, Laurence Mabile, Saman Khalatbari-Soltani, Cyrille Delpierre, Michelle Kelly-Irving
Journal: Environmental Health Perspectives (2022)

Background: Exposome research aims to describe and understand the extent to which all the exposures in human environments may affect our health over the lifetime. However, the way in which humans interact with their environment is socially patterned. Failing to account for social factors in research exploring the exposome may underestimate the magnitude of the effect of exposures or mask inequalities in the distribution of both exposures and outcomes. Objectives: We aimed to describe the extent to which social factors appear in the exposome literature, the manner in which they are used in empirical analyses and statistical modeling, and the way in which they are considered in the overall scientific approach. Methods: We conducted a scoping review of the literature using three databases (PubMed, Embase, and Web of Science) up to January 2022. We grouped studies based on the way in which the social variables were used in the analyses and quantified the type and frequency of social variables mentioned in the articles. We also qualitatively described the scientific approach used by authors to integrate social variables. Results: We screened 1,001 records, and 73 studies were included in the analysis. Fifty-five (∼75%) used social variables as exposures or confounders or both, and a wide array of social variables were represented in the articles. Individual-level social variables were more often found, especially education and race/ethnicity, as well as neighborhood-level deprivation indices. Half of the studies used a hypothesis-free approach and the other half, a hypothesis-driven approach. However, in the latter group, of 35 studies, only 8 reported and discussed at least one possible social mechanism underlying the relationship observed between the social variable and the outcome. Discussion: Social factors in exposome research should be considered in a more systematic way, considering their role in structuring both the specific external and the internal exposome. Doing so could help to understand the mechanisms of construction and, potentially, alleviate social inequalities in health and mitigate the emergence of new ones. https://doi.org/10.1289/EHP11015
Head-to-head comparison of 4 hyaluronic acid dermal fillers for lip augmentation: A multicenter randomized, quadruple-blind, controlled clinical trial
Authors: Serge A. Steenen, Constantijn G. Bauland, Berend van der Lei, Naichuan Su, Muriëlle D.G. van Engelen, Rachella D.R.R.A.L. Anandbahadoer-Sitaldin, Whitney Koeiman, Tina Jawidan, Yama Hamraz, Jan de Lange
Journal: Journal of the American Academy of Dermatology (2022)
Can dementia risk be reduced by following the American Heart Association's Life's Simple 7? A systematic review and dose-response meta-analysis
Authors: Jing Wu, Ying Xiong, Xin Xia, Nicola Orsini, Chengxuan Qiu, Miia Kivipelto, Debora Rizzuto, Rui Wang
Journal: Ageing Research Reviews (2022)

This study aimed to quantify the relationships between the American Heart Association (AHA) Cardiovascular Health (CVH) metrics, namely AHA Life’s Simple 7, and cognitive outcomes. We searched PubMed and Embase (January 1, 2010—August 24, 2022) and finally included 14 longitudinal studies (311654 participants with 8006 incident dementia cases). Random-effects meta-analysis and one-stage linear mixed-effects models were performed. Increased CVH score seemed to associate with decreased risk of incident dementia in a linear manner, but this relationship varied by the measurement age of CVH metrics. That is, midlife CVH tended to have a linear association with late-life dementia risk, whereas a J-shaped association was observed between the late-life CVH score and dementia. In addition, late-life dementia risk was reduced significantly if individuals maintained an ideal level of AHA’s CVH guidelines of physical activity, fasting plasma glucose, total cholesterol, and smoking. However, our meta-analysis did not show a significant association between CVH score and global cognitive decline rate. Following AHA’s CVH guidelines and maintaining CVH at an optimal level would substantially reduce the late-life dementia risk. More research is required to explore the link between a favorable CVH score and cognitive trajectories among cognitively asymptomatic older populations.
Modulators of ASIC1a and its potential as a therapeutic target for age-related diseases
Authors: Ren-Peng Zhou, Hong-Yu Liang, Wei-Rong Hu, Jie Ding, Shu-Fang Li, Yong Chen, Ying-Jie Zhao, Chao Lu, Fei-Hu Chen, Wei Hu
Journal: Ageing Research Reviews (2022)
The role of stem cells in small-cell lung cancer: Evidence from chemoresistance to immunotherapy
Authors: Wenwen Guo, Tianyun Qiao, Tian Li
Journal: Seminars in Cancer Biology (2022)

Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, accounting for approximately 15 % among all lung cancers. Despite the ability of chemotherapy, the first-line treatment for SCLC, to rapidly shrink tumors, nearly all patients experience recurrence and metastasis within a few months. Cancer stem cells (CSCs) are a small population of tumor cells responsible for tumorigenesis, metastasis, and recurrence after treatment, which play a crucial role in chemoresistance by promoting DNA repair and expression of drug resistance-associated proteins. Thus, targeting CSCs has been successful in certain malignancies. Tumor therapy has entered the era of immunotherapy and numerous preclinical trials have demonstrated the effectiveness of immunotherapeutic approaches targeting CSCs, such as tumor vaccines and chimeric antigen receptor (CAR) T cell, and the feasibility of combining them with chemotherapy. Therefore, a deeper understanding of the interaction between CSCs and immune system is essential to facilitate the advances of new immunotherapies approaches targeting CSCs as well as combination with standard drugs such as chemotherapy. This narrative review summarizes the mechanisms of chemoresistance of CSCs in SCLC and the latest advances in targeted therapies. Thereafter, we discuss the effects of CSCs on tumor immune microenvironment in SCLC and corresponding immunotherapeutic approaches. Eventually, we propose that the combination of immunotherapy targeting CSCs with standard drugs is a promising direction for SCLC therapies.
Advisory Board and Contents
Authors: Matthew Botvinick, Nick Chater, Floris De Lange, Lea-Maria Schmitt, Micha Heilbron, Andreas Engel, Christian Gerloff, Chris Frith, Uta Frith, Catherine Hartley, Lindsey Drayton, Danielle Loughlin, Rolf Van Der Sanden, Patrick Scheffmann, Ralph Adolphs, Renee Baillargeon, Roshan Cools, Lila Davachi, Peter Dayan, Stanislas Dehaene, Daniel Dennett, Yadin Dudai, Martha Farah, Angela Friederici, Okihide Hikosaka, Ray Jackendoff, Philip Johnson-Laird, Nancy Kanwisher, Christof Koch, Marta Kutas, Nikos Logothetis, James Mcclelland, Earl Miller, Elizabeth Phelps, Russell Poldrack, Marcus Raichle, Trevor Robbins, Laurie Santos, Anthony Wagner, Vincent Walsh
Journal: Trends in Cognitive Sciences (2022)
Combination cancer immunotherapies: Emerging treatment strategies adapted to the tumor microenvironment
Authors: Nicole Kirchhammer, Marcel P. Trefny, Priska Auf der Maur, Heinz Läubli, Alfred Zippelius
Journal: Science Translational Medicine (2022)

Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, resistance to ICB occurs frequently due to tumor-intrinsic alterations or extrinsic factors in the tumor microenvironment. This Viewpoint aims to give an update on recent developments in immunotherapy for solid tumors and highlights progress in translational research and clinical practice.
Advancing beyond the twists and turns of T cell exhaustion in cancer
Authors: Verena van der Heide, Etienne Humblin, Abishek Vaidya, Alice Oliffson Kamphorst
Journal: Science Translational Medicine (2022)

Chronic antigen stimulation leads to T cell exhaustion. Nutrient restrictions and other suppressive factors in the tumor microenvironment further exacerbate T cell dysfunction. Better understanding of heterogeneity and dynamics of exhausted CD8 T cells will guide novel therapies that modulate T cell differentiation to achieve more effective antitumor responses.
Translating the evolving molecular landscape of tumors to biomarkers of response for cancer immunotherapy
Authors: Valsamo Anagnostou, Blair V. Landon, Jamie E. Medina, Patrick Forde, Victor E. Velculescu
Journal: Science Translational Medicine (2022)

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapeutics, triggering studies to understand the molecular and cellular wiring of response and resistance. Our increased understanding of the underlying biology of response to ICI has enabled the investigation of tumor-intrinsic and -extrinsic features that may predict therapeutic outcomes. In parallel, liquid biopsy measurements of circulating tumor DNA (ctDNA) can be used to assess real-time molecular responses and guide clinical decisions during ICI. The combination of these approaches provides a deeper understanding of cancer biology, immunoediting, and evolution during ICI and promise to extend the utility of immunotherapies for patients with cancer.
Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies
Authors: Daniel B. Goodman, Camillia S. Azimi, Kendall Kearns, Alexis Talbot, Kiavash Garakani, Julie Garcia, Nisarg Patel, Byungjin Hwang, David Lee, Emily Park, Vivasvan S. Vykunta, Brian R. Shy, Chun Jimmie Ye, Justin Eyquem, Alexander Marson, Jeffrey A. Bluestone, Kole T. Roybal
Journal: Science Translational Medicine (2022)

Chimeric antigen receptors (CARs) repurpose natural signaling components to retarget T cells to refractory cancers but have shown limited efficacy in persistent, recurrent malignancies. Here, we introduce “CAR Pooling,” a multiplexed approach to rapidly identify CAR designs with clinical potential. Forty CARs with signaling domains derived from a range of immune cell lineages were evaluated in pooled assays for their ability to stimulate critical T cell effector functions during repetitive stimulation that mimics long-term tumor antigen exposure. Several domains were identified from the tumor necrosis factor (TNF) receptor family that have been primarily associated with B cells. CD40 enhanced proliferation, whereas B cell–activating factor receptor (BAFF-R) and transmembrane activator and CAML interactor (TACI) promoted cytotoxicity. These functions were enhanced relative to clinical benchmarks after prolonged antigen stimulation, and CAR T cell signaling through these domains fell into distinct states of memory, cytotoxicity, and metabolism. BAFF-R CAR T cells were enriched for a highly cytotoxic transcriptional signature previously associated with positive clinical outcomes. We also observed that replacing the 4-1BB intracellular signaling domain with the BAFF-R signaling domain in a clinically validated B cell maturation antigen (BCMA)–specific CAR resulted in enhanced activity in a xenotransplant model of multiple myeloma. Together, these results show that CAR Pooling is a general approach for rapid exploration of CAR architecture and activity to improve the efficacy of CAR T cell therapies.